The delayed and cumulative effects of continuous administration of drugs of abuse can be studied conveniently in rats implanted with slow-release silicone pellets containing amphetamines, or hallucinogens, or barbiturates, or ethanol, or phencyclidine. In previous research we have observed several stages of behavior following implantation of continuous-release amphetamine pellets, including a late stage which does not apparently occur with repeated daily injections. We have also found that this continuous amphetamine intoxication uniquely produces alterations in brain dopamine terminals indicative of long-lasting or permanent damage. In further studies we wish to better characterize this damage using fluorescence microscopy, assays of monoamine levels, regional determinations of tyrosine and tryptophan hydroxylase activity, and measures of uptake and receptor binding. We also propose to determine whether this long-term damage can be altered by the concurrent administration of tranquilizers, neuroleptics, or other drugs of abuse, and whether recovery from this damage can be facilitated by enriched environmental housing. In other studies we will determine whether continuous administration of hallucinogens, barbiturates, or ethanol also results in neurotoxic effects, and specify the exact brain regions and neurochemical pathways involved. We will also describe the late behavioral stages during continuous drug administration and upon drug withdrawal, and study if the concurrent administration of two different drugs summates for neurotoxicity. These experiments represent a novel approach to the study of chronic drug administration and will result in the development of convenient, inexpensive silicone pellets of general use for researchers of chronic drug administration and of dependence.